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Sub-Saharan Africa (SSA) continues to bear a disproportionate global disease burden while also facing significant disparities in research productivity and impact. As such, strengthening the research capacity in SSA is an urgent priority, necessitating a multifaceted assessment of the current landscape, the role of international collaboration and the alignment of research efforts with health needs. In this study, we conducted a macro-level bibliometric analysis to assess research capacity, thematic alignment and structural autonomy in SSA. We found that SSA accounted for approximately 15% of the global population and 21% of the global disease burden, yet it received only 2.7% of global citations in 2021. Despite increasing the research output over time, academic impact and leadership remain limited. Higher international collaboration rates were positively associated with a higher research impact, but also with a markedly greater proportion of publications without SSA researchers in key authorship positions, indicating persistent structural dependency. Researcher autonomy in SSA was substantially lower than in other regions, though slight improvements were observed during the COVID-19 period. Meanwhile, the Burden-Adjusted Research Intensity analysis showed a disproportionate concentration of research on HIV/AIDS, tuberculosis and malaria. This focus was sustained—and even intensified—in SSA during the pandemic, while many other high-burden diseases, including neglected tropical diseases, remained severely under-researched. In conclusion, this study provides quantitative evidence of persistent academic dependency and misaligned research priorities in SSA, with our analyses revealing how structural inequities in international collaborations and externally driven research agendas limit local research leadership and potentially hinder effective responses to regional health needs. Achieving a more just global research ecosystem demands active decolonisation efforts centred on empowering Global South ownership, including genuinely equitable partnerships, the reform of funding mechanisms to prioritise locally led research, and sustained investment in developing local research and leadership capacity.